Lower respiratory infection is one of the leading causes of human death worldwide, and is the most important cause of mortality in infants. Among the pathogens responsible for these infections, human respiratory syncytial virus (RSV) accounts for approximately 20% of all lower respiratory infections in infants. The global incidence of infant mortality due to RSV is the highest in developing countries, and though it is much lower in developed countries, it is a high burden on the health care systems because of the large number of children that must be hospitalized. RSV can also cause fatal respiratory tract infections in fragile or immune-compromised individuals. Recently, RSV has been recognized as a significant cause of severe respiratory infections in the elderly. In a study performed in the US, the mortality rates were found to be higher in the elderly than in the children (Thompson et al., 2003). No vaccine is presently available against RSV, even if many trials have been done. Due to the immunopathological component of the symptoms, immunization with this virus is challenging, especially in the very young population. Treatment options are limited to the prophylactic treatment of at-risk infants with the mAb palivizumab (Synagis®) and to controversial therapeutic intervention with the nucleoside analog ribavirin (Rebetol®) (Collins and Melero, 2011).
The RSV replication machinery has been the focus of some drug discovery research in the field of siRNA and small molecules. As for all paramyxoviruses, RSV uses a helical nucleocapsid containing the nucleoprotein N bound to genomic RNA, the polymerase cofactor P, the viral polymerase L and M2-1 matrix protein to modulate transcription and replication. Whereas N, P and L are sufficient to mediate viral replication, the transcriptional activity requires the M2-1 protein functioning as a processivity polymerase co-factor. The protein P plays a central role in both processes. First, P functions as a chaperone by binding to freshly synthesized nucleoprotein thereby maintaining N in a RNA unbound form, named N0. This N0-P complex is required for efficient and specific encapsidation of the viral genome and antigenome by N. Second, P mediates specific recognition of the viral nucleocapsid by the L polymerase, to initiate viral transcription and replication (Mason et al., 2003; Tran et al., 2009). P is a phosphoprotein of 241 aa, which has been previously characterized (Castagné et al., 2004). Except for the central domain which mediates oligomerization, the P protein is poorly structured in its N-terminal (residues 1-103) and C-terminal (200-241) regions. Antiviral approaches aimed at disrupting viral protein-protein interactions are emerging as a viable strategy (Castel et al., 2009; Wunderlich et al., 2011). However, all these strategies rely on native peptides that are known to have important drawbacks.
Therefore, new and improved strategies for the treatment and/or prevention of RSV infection are still required.